1. Field of the Invention
The present invention relates to a process for producing substituted amines useful as synthetic intermediates for medicine and agricultural chemicals as well as to a method for purifying synthetic intermediates therefor.
2. Description of the Prior Art
Generally, a process for producing alkoxyalkylamines from hydroxylamine or a salt thereof involves reaction of a chloroformate with a hydroxylamine salt in the presence of sodium hydroxide and subsequent alkylation with a dialkyl sulfate in the presence of sodium hydroxide, followed by hydrolysis.
For example, a process for producing methoxymethylamine is known as described in Org. Prep. Proced., 19, 75 (1987). In this prior art process, hydroxylamine hydrochloride is allowed to react with ethyl chloroformate in an aqueous solution of sodium hydroxide to form ethyl hydroxycarbamate which is then dimethylated with dimethyl sulfate in an aqueous solution of sodium hydroxide, followed by hydrolysis with hydrochloric acid, whereby methoxymethylamine hydrochloride is obtained in 70% yield.
DE3245503 discloses a process for producing methoxymethylamine via butyl N,O-dimethylcarbamate as an intermediate. According to this prior art process, the starting material hydroxylamine sulfate is allowed to react with butyl chloroformate in the presence of sodium hydroxide to form butyl hydroxycarbamate which is then subjected to the steps of extraction with dichloromethane and of drying, and after the solvent is distilled off, said butyl hydroxycarbamate is dimethylated with dimethyl sulfate in an aqueous solution of sodium hydroxide, followed by hydrolysis with hydrochloric acid, whereby methoxymethylamine hydrochloride is obtained in 65% yield.
With respect to the synthesis of hydroxamic acids, conventional processes involve reaction of carboxylates with hydroxylamine or a salt thereof, or reaction of acid halides or acid anhydrides with hydroxylamine or a salt thereof (EP306936, An. Quim., 72, 683 (1976), ZL. Prikl. khim., 45, 1895 (1972), "Kagaku Daijiten" (Encyclopedic Dictionary of Chemistry) published by Tokyo Kagaku Dojin K. K.). However, there is no suggestion of conversion of the resulting hydroxamic acids into alkoxyalkylamines.
The prior art processes with chloroformates as the starting material have the problem that the yield of the product, alkoxyalkylamines, is too low for applicability in industry.
With respect to the production of alkoxyamines, the following 3 processes are known:
(1) A process in which benzaldoxime obtained by reacting benzaldehyde with hydroxylamine is O-alkylated with an alkylating agent and then hydrolyzed (J. Org. Chem., 32, 261 (1967));
(2) A process in which hydroxylamine disulfonate is O-alkylated with an alkylating agent and then hydrolyzed (Berichte, 53, 1477 (1920)); and
(3) A process in which hydroxylamine-O-sulfonic acid is methoxylated with sodium methoxide (EU Pat. 0341693).
Of these 3 processes already reported, the process (1) has the disadvantage of the low yield of the product because of the occurrence of N-alkylation of benzaldoxime that proceeds competitively with O-alkylation. The process (2) has the disadvantage that a large amount of inorganic waste is discharged as a source of environmental pollution. The process (3) has the disadvantage that the production cost is raised by the use of expensive hydroxylamine-O-sulfonic acid.
Conventional processes for producing N,O-dimethylhydroxylamine involve conversion of hydroxylamine into hydroxycarbamate and subsequent dimethylation thereof, followed by decarboalkoxylation (Japanese Laid-Open Patent Publication No. 56757/1994) or reaction of nitrite, bisulfite and SO.sub.2 to form sulfonimide from which N,O-dimethylhydroxylamine is obtained (FR Patent Publication No. 1377470 A (Laid Open)). Of these processes, the process described in FR Patent Publication No. 1377470 A is disadvantageous as an industrial process because of the discharge of a large amount of waste liquid, while the process described in Japanese Laid-Open Patent Publication No. 56757/1994 cannot be said an effective process because of the environmental pollution and high production costs resulting from the step of extracting an intermediate, N,O-dimethylhydroxycarbamate, with an organic solvent such as halogenated hydrocarbons. Furthermore, since this step brings about simultaneous extraction of O-methylhydroxycarbamate formed as by-product during the formation of N,O-dimethylhydroxycarbamate, there results the contamination of N,O-dimethylhydroxylamine with O-methylhydroxylamine after deprotection. The close boiling points of the two compounds (42.3.degree. C. for N,O-dimethylhydroxylamine and 48.1.degree. C. for O-methylhydroxylamine) make their purification through distillation very difficult, and therefore their separation requires multistage distillation columns.
U.S. Pat. No. 3,230,260 discloses a method for purifying a final product N,O-dimethylhydroxylamine, in which formaldehyde is added at pH 7 or less to O-methylhydroxylamine contained in N,O-dimethylhydroxylamine to convert it into gaseous O-methylformaldehydeoxime so that O-methylhydroxylamine can be removed.
However, the removal of O-methylhydroxylamine in the method described in U.S. Pat. No. 3,230,260 must undergo the complicated steps of extracting with an organic solvent such as halogenated hydrocarbons etc. an intermediate N,O-dimethylhydroxamic acid and by-products including O-methylhydroxamic acid from an aqueous solution containing inorganic salts etc., concentrating the extraction solvent, deprotecting the products, and adding formaldehyde to convert O-methylhydroxylamine into gaseous O-methylformaldehydeoxime which is then separated. Furthermore, the halogenated hydrocarbon solvent for extraction and formaldehyde for conversion are highly toxic, and in particular, formaldehyde is extremely difficult to handle with its maximum permissible concentration being as low as 2 ppm as specified in the law. Furthermore, the high water-solublity of formaldehyde makes recovery of unreacted formaldehyde difficult. In addition, the recovery of O-methylformaldehydeoxime formed requires facilities of high cooling efficiency because of its low boiling point (-12.degree. C.), and therefore the facilities and the complicated procedures cost much.